(1S,2S,5S)-2-hydroxy-5-(6-methoxy-2-naphthyl-alpha, alpha, 1- trimethylcyclopentaneethanol

ABSTRACT

Preparation and the unexpected estrogenic activity of (1S,2S, 5S)-2-hydroxy-5-(6-methoxy-2-naphthyl)- Alpha , Alpha ,1trimethylcyclopentaneethanol are disclosed.

United States Patent [1 1 Chinn (lS,2S,5S)-2-I-IYDROXY-5-(6-METHOXY-2-NAPHTI-IYL-ALPI-IA, ALPHA, l- TRIMETHYLCYCLOPENTANEETHANOL [75]Inventor: Leland J. Chinn, Morton Grove, Ill.

[73] Assignee: G. D. Searle & Co., Chicago, 111.

[22] Filed: June 18, 1973 [21] Appl. No.2 370,837

OTHER PUBLICATIONS Brain et al., J. Chem. Soc. (C), pp. 3846-3851,

451 Apr. 15, 1975 1971 Bentley, .1. Chem. Soc., pp. 2398-2402, (1955).

Chinn et al., J. Org. Chem, 27, pp. 1733-1741, (1962).

Cambie et al.,;J. Chem. Soc. (C), PP. 2603-2608, (1968).

Primary ExaminerBernard I-1e1fin Assistant Examiner-Nicky Chan Attorney,Agent, or Firm.1ohn M. Brown [5 7] ABSTRACT Preparation and theunexpected estrogenic activity of(1S,2S,5S)-2-hydroxy-5-(6-methoxy-2-naphthy1)-a,a,1-trimethylcyclopentaneethanol are disclosed.

1 Claim, No Drawings 1 (1S,2S,SS)-2-HYDROXY-5-(6-METHOXY-2-NAPHTHYL-ALPHA, ALPHA, 1- TRIMETHYLCYCLOPENTANEETHANOL This inventionrelates to (18.28.58)-2-hydroxy-5-(6- nethoxy-Z-naphthyl )-a.a. l-trimethylcyclopentaneethanol, and to processes for the preparationthereof. The said product. which can be depicted by the formula isuseful because of its estrogenic activity. In the standardized test forsuch activity described in U.S. Pat. No. 3.501.506. l-S.2S,5S)-2hydroxy--(6-methoxy-2- naphthyl)- a.a.l-trimethylcyclopentaneethanol isactive at a dose of 1 mg. when administered subcutaneously. Thoseskilled in the art will recognize that observations of activity instandardized tests for particular biological effects are fundamental tothe development of valuable new drugs. both veterinary and human.-

The estrogenicity of the product of this'invention is whollyunforeshadowed by the prior art. Both lS.2S.5-R)-2-hydroxy-5-(6-methoxy-2-naphthyl)-a.a.2-trimethylcyclopentaneethanol and its Z-epimer. which are isomers of theinstant product described in J. Org. Chem.. 27. 1733 (I962). have beenfound to be inactive at 1 mg. subcutaneously in the aforesaid test.Likewise found inactive in this test are lS,2R.5R)-2-ethyl-2-hydroxy-5-(6-methoxy-2-naphthyl)-a,a-dimethylcyclopentaneethanol, anadjacent homolog of the latter prior art compound prepared by contactinglS,2R,5S-)-2-ethynyl-2-hydroxy-5-(6-methoxy-2-naphthyl)cyclopentaneacetic acidlactone [.l. Org. Chem.. loc. cit.] with methylmagnesium bromide inethyl ether. hydrolyzing the resultant Grignard complex with dilutehydrochloric acid to produce (lS.2R,5R)-2-ethynyl-2-hydroxy-5-(6-methoxy-2-naphthyl)-a,a-dimethylcyclopentaneethanol. andhydrogenating the latter compound at up to 3 atmospheres overpalladium-oncharcoal. Also inactive at 1 mg. subcutaneously in theforegoing test are (lS.2S, 5R)-2-ethyl-2-hydroxy-5-(6-methoxy-2-naphthyl )-a.a, l -trimethylcyclopentaneethanol. the 2-ethylanalog of the product of this invention; andlS,2R,5S)-2-ethyl-2-hydroxy-5-(6-methoxy- Z-naphthyl )-a.a.l-trimethylcyclopentaneethanol. the 2-epimer of the latter compound.(lS.2S.5R)-2-Ethyl- 2-hydroxy-5-(6-methoxy-2-naphthyl)-a,a-l-trimethylcyclopentaneethanol can be prepared by resolving d.l-5-(6-methoxy-2-naphthyl)-l-methyl-2-oxocyclopentaneacetic acid [theproduct of Example 4 in S. Africa 67/2807] with an optically activebase, contacting the resultant lS.5S) enantiomer with ethylmagnesiumbromide and acetylene in tetrahydrofuran. hydrolyzing acid, andcontacting the resultant ethynyl-2-hydroxy-5-( 6-methoxy-2-naphthyl lmethylcyclopentaneacetic acid with 2,2-dimethoxypropane to afford themethyl ester, from which the desired product eventuates by consecutivetreatment with methylmagnesium bromide and dilute hydrochloric acid toproduce (lS.2S,5S)-2-ethynyl-2-hydroxy-5-(6-methoxy-2-naphthyl)-a.a.l-trimethylcyclopentaneethanol and hydrogenationof the latter compound at up to 3 atmospheres overpalladium-on-charcoal. (1S.2S,-5S)-2-Ethyl-2-hydroxy-5-(6-methoxy-2-naphthyl)-a,a,l-trimethylcyclopentaneethanol can be prepared by hydrogenating(lS.2S.5S)-2-ethynyl-2-hydroxy-5- (6-methoxy-2-naphthyll-methylcyclopentaneacetic acid at up to 3 atmospheres overpalladium-oncharcoal, epimerizing the substituents on carbon atom number2 of the cyclopentane ring in the lS,2S,5S)-2- ethyl-2-hydroxy-5-(6-methoxy-2-naphthyl l methylcyclopentaneacetic acid thus obtained bywarming in a 10 percent solution (V/V) of sulfuric acid 'intetrahydrofuran, and consecutively treating the resultant(lS.2R.5S)-2-ethyl-2-hydroxy-5-(6-methoxy-2-naphthyl)-1-methylcyclopentane acetic acid lactone with methylmagnesiumbromide and dilute hydrochloric acid as above.

The preparation of lS.2S.5S)-2-hydroxy 5-(6- methoxy-Z-naphthyl )-a.a, l-trimethylcyclopentaneethanol proceeds by contactinglS.2S.5S)-2-acetoxy-5- 1,2,3 ,4-tetrahydro-6-methoxyl -oxo-2-naphthyl lmethylcyclopentaneacetic acid [1. Chem. Soc.. Sec. C. 1968. 2603] withsodium tetrahydroborate( 1-) in cold 2-propanol. heating the resultantlS.2S.5S)-2- acetoxy5-( 1.2.3.4-tetrahydrol -hydroxy-6-methoxy-2-naphthyl)-l-methylcyclopentaneacetic acid and/or corresponding lactonewith selenous acid in ethanol. esterifying the(lS.2S.5S)-2-acetoxy-5-(1.2.3.4- tetrahydro-6-methoxy-Z-naphthyl l-methylcyclopentane acetic acid thus obtained with diazomethane in coldethyl ether. contacting the ester with methylmagnesium bromide in ethylether. and finally hydrolyzing the resultant Grignard complex withdilute hydrochloric acid to produce the desired product.

The following examples describe in detail compounds illustrative of thepresent invention and methods which have been devised for theirpreparation. It will be apparent to those skilled in the art that manymodifications. both of materials and of methods. may be practicedwithout departing from the purpose and intent of this disclosure.Throughout the examples hereinafter set forth. temperatures are given indegrees Centigrade and relative amounts of materials in parts by weight.except as otherwise noted.

EXAMPLE 1 A.(lS.2S.5S)-2-Acetoxy-5-(1.2.3.4-tetrahydro-lhydroxy-6-methoxy-2-naphthyl)-l-methylcyclopentaneaceticacid and corresponding lactone To a stirred solution of approximately 10parts of l- S.2S.5S)-2-acetoxy-5-(l.2.3,4-tetrahydro-6-methoxyl-oxo-2-naphthyl l -methylcyclopentaneaceticacid in parts of 2-propanol at around 5 is added 2 parts of sodiumtetrahydroborate( l-). Stirring at 5 is continued for 1 hour, whereuponthe reaction mixture is allowed to stand at room temperatures for 15hours. At this point, 2 parts of glacial acetic acid is introduced; andthe resultant mixture is stripped of liquid by vacuum distillation. Tothe residue is added 500 parts of water. The oily component of the2-phase mixture thus obtained solidifies on stirring. The solid iscollected on a filter, washed thereon with water, and dried in air. Thisproduct is a mixture of (lS,2S,5S)-2-acetoxy-5- l,2,3,4-tetrahydrol-hydroxy-6-methoxy-2- naphthyl)-l-methylcyclopentaneacetic acid and thecorresponding lactone.

B. lS,2S,5S)-2-Acetoxy-5-( l.2,3,4-tetrahydro- 6-methoxy-2- naphthyl l-methylcyclopentaneacetic acid To a solution of parts oflS.2S,5S)-2-acetoxy-5- l,2,3.4-tetrahydrol -hydroxy-6-methoxy-2-naphthyl)-l-methylcyclopentaneacetic acid, alone or admixed with thecorresponding lactone as isolated in Example 1A, in 120 parts of ethanolis added 5 parts of selenous acid. The resultant mixture is heated atthe boiling point under reflux for l /2 hours, whereupon insolublesolids are filtered out and the filtrate stripped of solvent by vacuumdistillation. The residue is mixed with 1,000 parts of water, thenallowed to stand at 5 for 1 hour. Insoluble solids are filtered out,washed with water. and dried in air. The product thus isolated is 1-5,128.58 )-2-acetoxy-5-( l ,2,3,4-tetrahydro-6-methoxy- Z-naphthyl l-methylcyclopentaneacetic acid which, recrystallized from ether, meltsat approximately ll52.

C. Methyl lS,2S,5S)-2-acetoxy-5-( l.2,3,4-tetrahydro-6-methyl-Z-naphthyl l -methylcyclopentaneacetate To a mixture of 6 parts of(lS.2S,5S)-2-acetoxy-5- l ,2,3.4-tetrahydro-6-methoxy-2-naphthyl)- lmethylcyclopentaneacetic acid and 70 parts of ether is added 3 volumesof an ice-cold solution of diazomethane in ethyl ether prepared from 35parts of N- nitrosomethylurea, 280 parts of ethyl ether, parts ofpotassium hydroxide, and 70 parts of water according to the proceduredescribed in Org. Syn., Coll. Vol. 2, page (1943). The resultant mixtureis maintained at 5 for 2 hours with occasional stirring, whereuponinsoluble solids are removed by filtration. The filtrate is stripped ofsolvent by vacuum distillation, and the residual oil is crystallizedfrom a mixture of ether and hexane to give methyl(lS,2S,5S)-2-acetoxy-5- 1,2,3,4-tetrahydro-6-methoXy-2-naphthyl)- lmethylcyclopentaneacetate melting at 79.5-84.5.

D. lS,2S,5S)-2-hydroxy-5-(6-methoxy-2-naphthyl)-01,01,l-trimethylcyclopentaneethanol To a solution of l0 parts of methyl(lS,2S ,5S)-2- acetoxy-5-( l,2',3,4-tetrahydro-6-methoxy-2-naphthyll-methylcyclopentaneacetate in parts of anhydrous ethyl ether is added asolution of 36 parts of methylmagnesium bromide in 70 parts of anhydrousethyl ether. The resultant mixture is stirred at room temperatures for15 hours, whereupon 250 parts of water is carefully introduced. Themixture thus obtained is acidified with 5 percent hydrochloric acid. Theether phase is then separated, washed with water. dried over anhydroussodium sulfate, and stripped of solvent by vacuum distillation. Theresidue is lS.2S,5- S)-2-hydroxy-5-(6-methoxy-2-naphthyl)-a,a,1-trimethylcyclopentaneethnaol which. crystallized from a mixture of etherand hexane, is a colorless solid melting at l88190.

What is claimed is:

l. (lS,2S.5S)-2-hydroxy-5-(6-methoxy-2-naphthyl)- a.a, l-trimethylcyclopentaneethanol.

1. (IS,2S,5S)-2-HYDROXY-5-(6-METHOXY-2NAPTHYL)-A,A,1TRIMETHYLCYCLOPENTANEETHANOL.